Since introduction of the triiodinated benzoic acid derivatives as opacifying compounds in X-ray contrast agents for the reproduction of blood vessels, the excretory urinary tract, and other body cavities and tissues, a large number of derivatives has been synthesized, tested, and, in part, also utilized in practice, in ionic contrast media in the form of their salts, as well as in nonionic contrast media.
In this connection, it has been found that the nonphysiologically high osmotic pressure of the salt preparations is responsible for a number of incompatibility phenomena, whereby the spectrum of indications of these preparations is limited. This has resulted in the development of nonionic iodine compounds of high water solubility, the osmotic pressure of which is considerably lower.
Metrizamide (U.S. Pat. No. 3,701,771) is regarded as the first well compatible, soluble nonionic opacifying compound suitable for practical radiology. In metrizamide, solubility is obtained by an amide bond of the triiodinated aromatic to glucosamine. In the case of ioglumide (GB 1,436,357), the same is attained by an amide bond of the triiodinated aromatic with gluconic acid. Compounds having such side chains are difficult to prepare, do not show sufficient stability for heat sterilization, and do not have adequate shelf life. This must be considered a grave disadvantage for their practical usage in X-ray contrast media.
Almost all of the aforedescribed nonionic compounds are derived from the two basic structures of triiododiaminobenzoic acid and triiodoaminoisophthalic acid. The existing derivatives of both basic compounds do not satisfy the ever increasing requirements to be met by an ideal X-ray contrast medium. The most important requirements are high contrast density, chemical stability and maximally complete [up to 100%] nontoxicity of the active agent, low viscosity of the liquid preparation, and suitable pharmacodynamic properties adapted to the form of administration. The "ideal contrast medium" should combine all of these requirements. On the other hand, it is known that, due to the requirements regarding contrast density, stability and viscosity, the possibilities of varying the two aforementioned basic structures are considerably restricted, especially also in view of the fact that, for practical usage, compounds having a high iodine content are generally considered. Since the possibilities of synthesizing such compounds have been extensively exhausted in the meantime, the introduction of a novel basic structure is of special value.
The relatively good compatibility of the X-ray contrast media used nowadays is attained by detoxifying the actually lipophilic and toxic basic compounds [i.e. structures] by strongly hydrophilic substitutes.